Product comprising a heterotrimeric g protein signal transduction inhibitor associated with anti-hypertensive agent for therapeutic use in the treatment of arterial hypertension

ABSTRACT

The invention concerns a product comprising at least an inhibitor of heterotrimeric G protein signal transduction, associated with at least another anti-hypertensive agent, in particular calcium channel blockers and conversion enzyme inhibitors, for simultaneous, separate or prolonged therapeutic use, in the treatment of hypertension.

[0001] The present invention relates to a product comprising at leastone G protein inhibitor, and preferably a compound of general formula(I) defined below, combined with at least one anti-hypertensive agent,preferably chosen from the group comprising calcium channel antagonistsor conversion enzyme inhibitors, for simultaneous, separate or spreadover time therapeutic use, in the treatment of arterial hypertension.

[0002] Arterial hypertension is a very common disease and one to which ahigh morbidity and mortality rate is associated. According to age,treatment of hypertension must be considered when the systolic arterialpressure is higher than 160-180 mm of mercury and the diastolic pressurehigher than 100-110 mm of mercury.

[0003] The optimum strategy for the care of patients suffereing fromhypertension is still under discussion. Non-pharmacological treatment(reduction of sodium intake in food, loss of weight, physical exercise,giving up tobacco products etc.) is a possibility in patients withmoderate hypertension. Pharmacological treatment begins withmonotherapy, which allows satisfactory blood pressure control in 50-60%of patients. Changing therapeutic class as well as combination withanother class of anti-hypertensive agents represent the alternativetreatments in the event of resistance to the first therapy (Beaufils andElement, Drugs, 56, 11-21, (1998)).

[0004] Anti-hypertensive medicaments can be divided into severalclasses:

[0005] thiazidic and similar diuretics such as hydrochlorothiazide,cicletanine, xipamide, indapamide and clopamide;

[0006] loop diuretics such as furosemide, piretanide and bumetanide;

[0007] hyperkalaemia causing (potassium-sparing) diuretics such asamiloride, spironolactone and canrenone;

[0008] beta-blockers such as propranolol, acebutolol, atenolol, nadolol,bisoprolol, metoprolol, pindolol, oxprenolol and betaxolol;

[0009] conversion enzyme inhibitors (CEI) such as captopril, enalapril,benazepril, lisinopril, quinapril, ramipril and imidapril;

[0010] Angiotensin II receptor antagonists (ARBs), such as losartan,candesartan, cilexetil, irbesartan, telmisartan, and valsartan;

[0011] Slow calcium channel antagonists, such as nifedipine, amlodipine,felodipine, isradipine, diltiazem, bepridil, lacidipine, nitrendipine,nicardipine and verapamil;

[0012] central anti-hypertensive agents such as clonidine, guanfacine,monoxidine, rilmenidine and α-methyl-dopa;

[0013] alpha-blockers such as prasozine, urapidil, doxazosine andterazosine;

[0014] vasodilators such as hydralazine, dihydralazine and minoxidil.

[0015] Furthermore, the development of new anti-hypertensive treatmentsof course involves the discovery of new molecules (cf. Singh et al,Drugs, 58(4):579-87 (October 1999); (Mancia et al, Curr. Opin. Cardiol.,14(5):375-80 (September 1999); Cases, Drug new Perspect., 12(6) 372-377(1999)). Among the new families of molecules intended for the treatmentof hypertension, the following can in particular be mentioned:

[0016] vasopeptidase inhibitors; and

[0017] endothelin antagonists.

[0018] More recently, allellic variations of the genes coding for theangiotensinogen, the β2-adrenergic receptor, and the β3 sub-unit of theG protein have been identified. (Luft, F. C., Journal of hypertension,16, 1871-1878, (1998)). In addition, the results of Anand-Srivastava(Mol. Cell. Biochem., 175, 163-170, (1996)) suggest that the increase inthe expression of the Gi α-2 and Gi α-3 proteins in the heart and theaorta which precedes the development of an increase in arterial pressurein the SHR rat (Spontaneously Hypertensive Rat) can be one of thefactors causing hypertension. Similarly, the βγ sub-units of the Gprotein seem to be involved in the control of the recurrence of stenosisand the proliferation of smooth vascular muscle cells (Iaccarino et al.,Proc. Nat. Acad. Sci. USA, 96, 3945-3950,(1999)). Blocking of thesesub-units by a βARKct peptide prevents proliferation. On the other hand,a Gi protein inhibitor, pertussic toxin, is capable of lowering thearterial pressure of the SHR rat by intravenous injection. This loweringof pressure is observed for two weeks and seems more marked in thehypertensive rat than in the normotensive rat (Kost et coll, Clinicaland Experimental Pharmacology and Physiology, 26, 449-455, (1999)).Similarly the renal vascular tonus in the SHR rat is modified bypertussic toxin with an increase in renal vascular flux and a reductionin renal vascular resistance.

[0019] Together, these recent works suggest that heterotrimeric Gprotein can represent a therapeutic target for the control ofhypertension by the development of products specifically targeting thistransduction signal. The G protein participates in the transmission ofsignals from outside the cell towards the interior thanks to itsinteraction with the receptors with seven transmemnbrane fields usingdifferent effectors including adenylate cyclase, C phospholipase or alsoionic canals (cf. Gilman, A. G., Biosci. Rep., 15, 65-97 (1995)).

[0020] The Applicant has furthermore described specific inhibitors ofsignal transduction by heterotrimeric G proteins in the PCT patentapplication WO 00/02558 (which describes the use of the compounds ofGeneral Formula (I) hereafter, already known as farnesyltransferaseinhibitors (cf. WO 97/30053), as inhibitors of the transduction ofheterotrimeric G protein signals) and WO 00/02881.

[0021] When the limit of the efficacy of monotherapy is reached, thediscovery of effective combinations of different therapeutic classes issought to combine the effect of each class and better combathypertension of multifactorial origin. For example, a combination usingbeta-blockers and calcic antagonists is effective in 80 to 85% of cases.This combination allows doses to be reduced in comparison to the dosesused in monotherapy.

[0022] The Applicant shows in the present Application that thecombination of a G protein inhibitor with another anti-hypertensiveagent, preferably an anti-hypertensive agent from another class, allowshypertension to be reduced more effectively. A product according to theinvention offers the advantage of allowing lower doses of theanti-hypertensive agents chosen to be used, which has the main effect ofreducing the side effects of the treatment whilst obtaining anequivalent therapeutic benefit.

[0023] A subject of the invention is therefore a product comprising atleast one inhibitor of the transduction of heterotrimeric G proteinsignals combined with at least one anti-hypertensive agent, preferablyan anti-hypertensive agent from another class, said anti-hypertensiveagent being preferably chosen from the group comprising calcium channelinhibitors and conversion enzyme inhibitors for simultaneous, separateor spread over time therapeutic use, in the treatment of arterialhypertension.

[0024] Preferably, a product according to the invention will comprise aheterotrimeric G protein signal transduction inhibitor corresponding togeneral formula (I)

[0025] corresponding to sub-formulae (I_(A)) or (I_(B)):

[0026] in which:

[0027] X represents R₁₂ and Y represents R₈, or X and Y complete a ringwith 6 members, X—Y together representing the —CH(R₈)—CH(R₉)— radical;

[0028] R₁ represents H, an alkyl or lower alkylthio radical;

[0029] R₂ and R₃ independently represent H or a lower alkyl radical;

[0030] R₄ represents H₂ or O;

[0031] R₅ represents H, or one of the lower alkyl, lower alkenyl, loweralkynyl, cycloalkyl, cycloalkylalkyl, aryl, lower arylalkyl, heterocycleor lower alkyl heterocycle radicals, these radicals being optionallysubstituted by radicals chosen from the group comprising a lower alkylradical, —O—R₁₀, —S(O)_(m)R₁₀ (m representing 0, 1, or 2), —N(R₁₀)(R₁₁),—N—C(O)—R₁₀, —NH—(SO₂)—R₁₀, —CO₂—R₁₀, C(O)—N(R₁₀)(R₁₁), and—(SO₂)—N(R₁₀)(R₁₁);

[0032] R₆ and R₇ independently represent H, a —C(O)—NH—CHR₁₃—CO₂R₁₄radical, or one of the lower alkyl, aryl, lower arylalkyl, lowerarylsulphonylalkyl, lower aralkoxyalkyl, heterocycle or lower alkylheterocycle radicals, these radicals being optionally substituted byradicals chosen from the group comprising OH, alkyl or lower alkoxy,N(R₁₀)(R₁₁), COOH, CON(R₁₀)(R₁₁), and halo radicals,

[0033] or R₆ and R₇ together form an aryl radical or a heterocycle;

[0034] R₈ and R₉ independently represent, H or one of the lower alkyl,aryl, lower arylalkyl, heterocycle or lower alkyl heterocycle radicals,these radicals being optionally substituted by radicals chosen from thegroup comprising the OH, alkyl or lower alkoxy, N(R₁₀)(R₁₁), COOH,CON(R₁₀)(R₁₁) and halo radicals,

[0035] or R₈ and R₉ together form an aryl radical or a heterocycle;

[0036] R₁₀ and R₁₁, independently represent H, an aryl radical orheterocycle, or an alkyl, arylalkyl or lower alkyl heterocycle radical;

[0037] R₁₂ represents NR₉, S, or O;

[0038] R₁₃ represents a lower alkyl radical optionally substituted by aradical chosen from the lower alkyl, —OR₁₀, —S(O)_(m)R₁₀ (m representing0, 1, or 2) and —N(R₁₀)(R₁₁) radicals;

[0039] R₁₄ represents H or a lower alkyl radical;

[0040] the compound of general formula (I) can if appropriate also bepresented in the dimer form of a disulphide;

[0041] or a pharmaceutically acceptable salt of a compound of generalformula (I) or if appropriate of its dimer.

[0042] By lower alkyl radical, is meant a linear or branched alkylradical containing 1 to 6 carbon atoms, and in particular the methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl,pentyl, neopentyl, isopentyl, hexyl, isohexyl radicals. By heterocycleradical, is meant a radical constituted by one or more rings andincluding at least one heteroatom (O, N or S). By aryl radical, is meanta carbocyclic mono- or polycyclic aromatic system comprising at leastone aromatic ring (and, in particular, the phenyl radical which can beabbreviated to Ph). By arylalkyl, alkyl heterocycle, alkylthio or loweralkoxy radical, is meant the radicals in which the alkyl radical has themeaning as indicated previously.

[0043] Preferably, the compounds of general formula (I) are such that:

[0044] X and Y complete a ring with 6 members, X—Y together representingthe —CH(R₈)—CH(R₉)— radical;

[0045] R₁ represents an alkyl or lower radical;

[0046] R₂ and R₃ represent H;

[0047] R₄ represents O;

[0048] R₅ represents H, or one of the lower alkyl, cycloalkyl,cycloalkylalkyl, lower arylsulphonylalkyl, lower aralkoxyalkyl radicals,these radicals being optionally substituted by radicals chosen from thegroup comprising a lower alkyl or —O—R₁₀ radical;

[0049] R₆ and R₇ represent independently H or an aryl radical optionallysubstituted by radicals chosen from the group comprising the OH, alkylor lower alkoxy radicals,

[0050] R₈ and R₉ represent H;

[0051] and R₁₀ and R₁₁, represent independently H or a lower alkylradical.

[0052] The following compounds of General Formula (I) are in particularpreferred for the invention:

[0053]7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-(2-methylphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;

[0054]7-(2-amino-1-oxo-3-thiopropyl)-8-butyl-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;

[0055]bis-1,1′-[7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methoxyphenyl)-8-(1-methylpropyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine]disulphide;

[0056]bis-1,1′-[7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazinedisulphide;

[0057]bis-1,1′-7-(2-amino-1-oxo-3-thiopropyl-(2-(1-naphthyl)-8-(2-methylpropyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazin-7-yl)disulphide;

[0058]7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-phenyl-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;

[0059]7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methoxyphenyl)-8-(phenylmethoxy)methyl-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;

[0060]7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methoxyphenyl)-8-(1-phenylmethoxy)ethyl-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;

[0061]7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methoxyphenyl)-8-(phenoxyethyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;

[0062]7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methoxyphenyl)-8-(phenoxyethyl)-5,6,7,8-tetrahydro-imidazo[1,2a]pyrazine,or its dimeric form;

[0063] and7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methoxyphenyl)-8-(phenylsulphonylethyl)-5,6,7,8-tetrahydro-imidazo[1,2a]pyrazine;

[0064] or a pharmaceutically acceptable salt of one of the latter.

[0065] As far as the anti-hypertensive agent combined with theheterotrimeric G protein signal transduction inhibitor is concerned,although the calcium channel inhibitors and the conversion enzymeinhibitors, and in particular verapamil and captopril, are preferred, anumber of other anti-hypertensive agents can also be used according tothe invention, such as thiazidic diuretics and substitutes, loopdiuretics, potassium-sparing diuretics, antialdosterones, beta-blockers,angiotensin receptor antagonists, anti-hypertensive agents,alpha-blockers and vasodilatatory agents, vasopeptidase inhibitors andendothelin antagonists.

[0066] According to a particularly preferred variant of the invention,the heterotrimeric G protein signal transduction inhibitor used in thecomposition of a product according to the invention is chosen from thefollowing compounds:

[0067]7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-phenyl-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;and

[0068]7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-(2-methylphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;

[0069] and pharmaceutically acceptable salts of the latter.

[0070] Still according to a particularly preferred variant of theinvention, anti-hypertensive agents combined with said inhibitors of thetransduction of heterotrimeric G protein signals are chosen from thegroup composed of:

[0071] calcium channel antagonists, and in particular verapamil;

[0072] conversion enzyme inhibitors, and in particular captopril;

[0073] and pharmaceutically acceptable salts of the latter.

[0074] Optionally, a second anti-hypertensive agent, different from theheterotrimeric G protein signal transduction inhibitor and theanti-hypertensive agent which is already combined with it, can becombined with a product according to the invention. Saidanti-hypertensive agent can be chosen from those already mentioned inthe present application. The following products are particularlypreferred, combining:

[0075] a heterotrimeric G protein signal transduction inhibitor, a loopdiuretic and hyperkalaemia causing diuretic;

[0076] a heterotrimeric G protein signal transduction inhibitor, athiazidic or related diuretic and a hyperkalaemia causing diuretic;

[0077] a heterotrimeric G protein signal transduction inhibitor, aconversion enzyme inhibitor and a thiazidic diuretic;

[0078] a heterotrimeric G protein signal transduction inhibitor, anangiotensin II receptor antagonist and a thiazidic diuretic;

[0079] a heterotrimeric G protein signal transduction inhibitor, abeta-blocker and a diuretic;

[0080] a heterotrimeric G protein signal transduction inhibitor, abeta-blocker and a calcium channel antagonist;

[0081] a heterotrimeric G protein signal transduction inhibitor, abeta-blocker and a vasodilatory agent.

[0082] A subject of the invention is also a pharmaceutical compositioncomprising a product according to the invention, with optionally one ormore pharmaceutically acceptable excipients.

[0083] The pharmaceutical compositions comprising a compound of theinvention can be in the form of solids, for example powders, granules,tablets, gelatin capsules, liposomes or suppositories. The appropriatesolid supports can be, for example, calcium phosphate, magnesiumstearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose,methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidineand wax.

[0084] The pharmaceutical compositions comprising a compound of theinvention can also be presented in liquid form, for example solutions,emulsions, suspensions or syrups. The appropriate liquid supports canbe, for example, water, organic solvents such as glycerol or glycols,and similarly their mixtures in varying proportions in water.

[0085] The administration of a medicament according to the invention canbe done by topical, oral, parenteral route, by injection (intramuscular,sub-cutaneous, intravenous, etc.), etc. The administration route will ofcourse depend on the type of disease to be treated.

[0086] The dose of a product according to the present invention, to beprovided for the treatment of the diseases or afflictions mentionedabove, varies according to the method of administration, the age and thebody weight of the subject to be treated as well as the condition of thelatter, and will be decided definitively by the attending doctor or vet.Such a quantity determined by the attending doctor or vet is referred tohere as “therapeutically effective amount”.

[0087] The following administration doses (daily, except where otherwiseindicated) can in particular be envisaged for the different compoundsused in the composition of a product according to the invention:

[0088] compound of General Formula (I): 0.1 to 100 mg/kg by intravenousroute; and 50 to 1000 mg orally per day in several doses

[0089] verapamil: 50 to 500 mg orally per day in several doses;

[0090] captopril: 50 to 500 mg orally per day in several doses.

[0091] For the other compounds used in the composition of the productsaccording to the invention, the daily administration doses are fixed bythe attending doctor or vet within the limit of doses of these compoundsusually administered for the treatment of arterial hypertension, whichcan in particular be found in a reference work (such as, for example,the Dictionnaire VIDAL®, the Rote Liste® or the Physician's DeskReference®).

[0092] Unless they are defined in another manner, all the technical andscientific terms used here have the same meaning as that usuallyunderstood by an ordinary specialist in the field to which thisinvention belongs. Similarly, all the publications, patent applications,all the patents and all other references mentioned here are incorporatedby way of reference.

[0093] The following examples are presented to illustrate the aboveprocedures and should in no way be considered as limiting the scope ofthe invention.

[0094] Preparation of the Compounds of General Formula (I) Used in theComposition of the 2Products of the Invention:

[0095] A) The compounds of General Formula (I) can be prepared accordingto methods similar to those described in PCT patent application WO97/30053.

[0096] B) The preparation of certain specific compounds of GeneralFormula (I), not described in PCT Application WO 97/30053, is describedin PCT Application WO 00/02881.

EXAMPLES

[0097] In order to illustrate the usefulness of the invention, theeffect on the arterial pressure of spontaneously hypertensive type ratsof treatment with7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-phenyl-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine(hereafter designated compound 2, described in Application WO 00/02881),combined with anti-hypertensive agents of two different classes, namelyconversion enzyme inhibitors (captopril) and calcium channel inhibitors(verapamil) will be studied.

[0098] 1) Procedures

[0099] 13/14 week old male SHR rats (Charles River France) areanaesthetized using pentobarbital (Sanofi) (60 mg/kg/IP). A carotidartery is catheterised for measuring arterial pressure and heart rate(Gould pressure and physiography sensors, Buxco acquisition softwareversion 1.5.7 and Analyst analysis software version 1.35 (EMKA)). Ajugular vein is catheterised for the injection of the anti-hypertensiveagent, compound 2 is injected into the vein of the penis. After astabilization period of 10 minutes, the product or two productssimultaneously are administered and their effects are monitored for 20minutes.

[0100] For administration purposes,7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-phenyl-5,6,7,8-tetrahydro-imidazo[1,2a]pyrazine,verapamil (Sigma, USA) and captopril (Sigma, USA) can be dissolved in anaqueous solution of NaCl at 0.9%.

[0101] The following groups (of 4 to 6 animals) are formed by:

[0102] compound 2 (1 mg/kg);

[0103] captopril (1 mg/kg);

[0104] verapamil (0.1 and 0.3 mg/kg);

[0105] captopril (1 mg/kg)+compound 2 (1 mg/kg);

[0106] verapamil (0.1 or 0.3 mg/kg)+compound 2 (1 mg/kg);

[0107] 2) Results:

[0108] The anaesthetized spontaneously hypertensive rats present anaverage arterial pressure varying between 165-190 mm. (cf. FIGS. 1, 2and 3).

[0109] Treatments by a single intravenous injection of the calciumchannel inhibitor verapamil (0.1 mg/kg or 0.3 mg/kg), or the conversionenzyme inhibitor captopril (1 mg/kg) or the heterotrimeric G proteininhibitor (1 mg/kg) lead to an immediate reduction (less than 2 minutes)in arterial pressure with a return to initial values 20 minutes afterthe injections are carried out at time 0 (FIG. 1).

[0110] Furthermore, the heart rates measured in these SHR rats,anaesthetized before injection, are between 328 and 371 beats perminute. The heart rates measured in these SHR rats treated with the sameproducts, shown in FIG. 2, are changed very little by these differenttreatments. Captopril does not change the heart rate at all, whilstverapamil (0.1 and 0.3 mg/kg) or the G protein inhibitor (1 mg/kg)induce a reduction with a maximum difference (delta) of 32, 56 and 44respectively.

[0111] The combination of several anti-hypertensive agents is frequentlyprescribed in order to obtain a stabilization of arterial pressure.

[0112] The combination of a G protein inhibitor and two othertherapeutic classes is illustrated below.

[0113]FIG. 3 shows that the “G protein inhibitor+captopril” combinationinduces a reduction in arterial pressure in the SHR rat higher than theactivity of the two products alone.

[0114] On the other hand, FIG. 4 shows that the G proteininhibitor+captopril combination does not induce a reduction in the heartrate in the SHR rat higher than the activity of the two products alone.

[0115]FIG. 5 shows that the “G protein inhibitor+verapamil” combinationinduces a reduction in arterial pressure in the SHR rat higher than theactivity of the two products alone. The “G protein inhibitor+verapamilcombination at a dose of 0.1 mg/kg” gives a profile similar to theaction of verapamil alone, but at a dose which is 3 times greater i.e.0.3 mg/kg (FIG. 5).

[0116] On the other hand, the results illustrated by FIG. 6 and thetable below show that the “G protein inhibitor+verapamil” combinationdoes not induce a reduction in the heart rate in the SHR rat higher thanthe activity of the two products alone. Dose(s) Product (mg/kg)Frequency difference (Δ) Compound 2 1 44 Captopril 1 1 Verapamil 0.1 28Verapamil 0.3 56 Compound 2 + captopril 1 and 1   25 Compound 2 + 1 and0.1 54 verapamil Compound 2 + 1 and 0.3 52 verapamil

1. Product comprising at least one heterotrimeric G protein signaltransduction inhibitor and at least one other anti-hypertensive agentfor simultaneous, separate or spread over time therapeutic use, in thetreatment of arterial hypertension.
 2. Product according to claim 1,characterized in that the other anti-hypertensive agent belongs to aclass other than that of the heterotrimeric G protein signaltransduction inhibitors.
 3. Product according to claim 1 or 2,characterized in that the heterotrimeric G protein signal transductioninhibitor is a compound corresponding to General Formula (I)

corresponding to sub-formulae (I_(A)) or (I_(B)):

in which: X represents R₁₂ and Y represents R₈, or X and Y complete aring with 6 members, X—Y together representing the —CH(R₈)—CH(R₉)—radical; R₁ represents H, an alkyl or alkylthio radical comprising from1 to 6 carbon atoms; R₂ and R₃ independently represent H or a loweralkyl radical; R₄ represents H₂ or O; R₅ represents H, or one of thealkyl radicals comprising from 1 to 6 carbon atoms, alkenyl comprisingup to 6 carbon atoms, alkynyl comprising up to 6 carbon atoms,cycloalkyl, cycloalkylalkyl the alkyl radical of which comprises from 1to 6 carbon atoms, aryl, arylalkyl the alkyl radical of which comprisesfrom 1 to 6 carbon atoms, heterocycle or alkyl heterocycle the alkylradical of which comprises from 1 to 6 carbon atoms, these radicalsbeing optionally substituted by radicals chosen from the groupcomprising an alkyl radical containing 1 to 6 carbon atoms, —O—R₁₀,—S(O)_(m)R₁₀ (m representing 0, 1, or 2), —N(R₁₀)(R₁₁), —N—C(O)—R₁₀,—NH—(SO₂)—R₁₀, —CO₂—R₁₀, C(O)—N(R₁₀)(R₁₁), and —(SO₂)—N(R₁₀)(R₁₁); R₆and R₇ independently represent H, a —C(O)—NH—CHR₁₃—CO₂R₁₄ radical, orone of the alkyl radicals comprising from 1 to 6 carbon atoms, aryl,arylalkyl the alkyl radical of which comprises from 1 to 6 carbon atoms,heterocycle or alkyl heterocycle the alkyl radical of which comprisesfrom 1 to 6 carbon atoms, these radicals being optionally substituted byradicals chosen from the group comprising the OH, alkyl or alkoxycomprising from 1 to 6 carbon atoms, N(R₁₀)(R₁₁), COOH, CON(R₁₀)(R₁₁),and halo radicals, or R₆ and R₇ together form an aryl radical or aheterocycle; R₈ and R₉ independently represent H or one of the alkylradicals comprising from 1 to 6 carbon atoms, aryl, arylalkyl the alkylradical of which comprises from 1 to 6 carbon atoms, heterocycle oralkyl heterocycle the alkyl radical of which comprises from 1 to 6carbon atoms, these radicals being optionally substituted by radicalschosen from the group comprising the OH, alkyl or alkoxy comprising from1 to 6 carbon atoms, N(R₁₀)(R₁₁), COOH, CON(R₁₀)(R₁₁) and halo radicals,or R₈ and R₉ form together an aryl radical or a heterocycle; R₁₀ andR₁₁, independently represent H, an aryl radical or heterocycle, or analkyl radical comprising from 1 to 6 carbon atoms, arylalkyl or alkylheterocycle the alkyl radical of which comprises from 1 to 6 carbonatoms; R₁₂ represents NR₉, S, or O; R₁₃ represents an alkyl radicalcomprising from 1 to 6 carbon atoms optionally substituted by a radicalchosen from the alkyl comprising from 1 to 6 carbon atoms, —OR₁₀,—S(O)_(m)R₁₀ (m representing 0, 1, or 2) and —N(R₁₀)(R₁₁) radicals; R₁₄represents H or an alkyl radical comprising from 1 to 6 carbon atoms; ora pharmaceutically acceptable salt of the latter.
 4. Product accordingto claim 3, characterized in that the compound of General Formula (I) issuch that: X and Y complete a ring with 6 members, X—Y togetherrepresenting the —CH(R₈)—CH(R₉)— radical; R₁ represents an alkyl radicalcomprising from 1 to 6 carbon atoms; R₂ and R₃ represent H; R₄represents O; R₅ represents H, or one of the alkyl comprising from 1 to6 carbon atoms, cycloalkyl, cycloalkylalkyl the alkyl radical of whichcomprises from 1 to 6 carbon atoms, arylsulphonylalkyl the alkyl radicalof which comprises from 1 to 6 carbon atoms, aralkoxyalkyl the alkoxyand alkyl radicals of which each comprise from 1 to 6 carbon atoms,these radicals being optionally substituted by radicals chosen from thegroup comprising an alkyl comprising from 1 to 6 carbon atoms or —O—R₁₀radical; R₆ and R₇ independently represent H or an aryl radicaloptionally substituted by radicals chosen from the group comprising theOH, alkyl or lower alkoxy radicals comprising from 1 to 6 carbon atoms,R₈ and R₉ represent H; and R₁₀ and R₁₁, independently represent H or analkyl radical comprising from 1 to 6 carbon atoms.
 5. Product accordingto claim 3 or 4, characterized in that the compound of General Formula(I) is one of the following compounds:7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-(2-methylphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;7-(2-amino-1-oxo-3-thiopropyl)-8-butyl-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;bis-1,1′-[7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methoxyphenyl)-8-(1-methylpropyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine]disulphide;bis-1,1′-[7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazinedisulphide;bis-1,1′-7-(2-amino-1-oxo-3-thiopropyl-(2-(1-naphthyl)-8-(2-methylpropyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazin-7-yl)disulphide;7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-phenyl-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methoxyphenyl)-8-(phenylmethoxy)methyl-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methoxyphenyl)-8-(1-phenylmethoxy)ethyl-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methoxyphenyl)-8-(phenoxyethyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methoxyphenyl)-8-(phenoxyethyl)-5,6,7,8-tetrahydro-imidazo[1,2a]pyrazine,or its form dimeric; and7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methoxyphenyl)-8-(phenylsulphonylethyl)-5,6,7,8-tetrahydro-imidazo[1,2a]pyrazine;or a pharmaceutically acceptable salt of one of the latter.
 6. Productaccording to claim 4, characterized in that the compound of GeneralFormula (I) is7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-phenyl-5,6,7,8-tetrahydro-imidazo[1,2a]pyrazineor a pharmaceutically acceptable salt of the latter.
 7. Productaccording to one of claims 1 to 6, characterized in that theanti-hypertensive agent combined with the heterotrimeric G proteinsignal transduction inhibitor is chosen from the group constituted bycalcium channel inhibitors, conversion enzyme inhibitors, thiazidicdiuretics and substitutes, loop diuretics, potassium-sparing diuretics,antialdosterones, beta-blockers, angiotensin receptor antagonists,anti-hypertensive agents, alpha-blockers and vasodilatory agents,vasopeptidase inhibitors and endothelin antagonists.
 8. Productaccording to claim 7, characterized in that the anti-hypertensive agentcombined with the heterotrimeric G protein signal transduction inhibitoris a calcium channel inhibitor.
 9. Product according to claim 8,characterized in that the anti-hypertensive agent combined with theheterotrimeric G protein signal transduction inhibitor is verapamil. 10.Product according to claim 7, characterized in that theanti-hypertensive agent combined with the heterotrimeric G proteinsignal transduction inhibitor is a conversion enzyme inhibitor. 11.Product according to claim 10, characterized in that theanti-hypertensive agent combined with the heterotrimeric G proteinsignal transduction inhibitor is captopril.
 12. Product according to oneof the previous claims, characterized in that it comprises moreover asecond anti-hypertensive agent, this one being different from theheterotrimeric G protein signal transduction inhibitor and from theanti-hypertensive agent which is already combined with it.
 13. Productaccording to claim 12, characterized in that the first anti-hypertensiveagent combined with the heterotrimeric G protein signal transductioninhibitor is a loop diuretic and the second is a hyperkalaemia causingdiuretic.
 14. Product according to claim 12, characterized in that thefirst anti-hypertensive agent combined with the heterotrimeric G proteinsignal transduction inhibitor is a thiazidic or related diuretic and thesecond is a hyperkalaemia causing diuretic.
 15. Product according toclaim 12, characterized in that the first anti-hypertensive agentcombined with the heterotrimeric G protein signal transduction inhibitoris a conversion enzyme inhibitor and the second is a thiazidic diuretic.16. Product according to claim 12, characterized in that the firstanti-hypertensive agent combined with the heterotrimeric G proteinsignal transduction inhibitor is an antagonist of angiotensin IIreceptors and the second is a thiazidic diuretic.
 17. Product accordingto claim 12, characterized in that the first anti-hypertensive agentcombined with the heterotrimeric G protein signal transduction inhibitoris a beta-blocker and the second is a diuretic.
 18. Product according toclaim 12, characterized in that the first anti-hypertensive agentcombined with the heterotrimeric G protein signal transduction inhibitoris a beta-blocker and the second is a calcium channel antagonist. 19.Product according to claim 12, characterized in that the firstanti-hypertensive agent combined with the heterotrimeric G proteinsignal transduction inhibitor is a beta-blocker and the second is avasodilatory agent.
 20. Pharmaceutical composition comprising at leastone heterotrimeric G protein signal transduction inhibitor and at leastone other anti-hypertensive agent, with optionally one or morepharmaceutically acceptable excipients.